Through hard work and inventiveness, molecular neuropharmacologist Philip Seeman transformed medical science’s understanding of schizophrenia and other brain conditions. He discovered the importance of the dopamine D2 receptor in 1974, showing that the schizophrenia drugs of that era – which were widely used but poorly understood – targeted this brain receptor.
His research led to a better understanding of schizophrenia and how to treat it. Dopamine and its receptors also play a key role in Parkinson’s and Huntington’s, and his discoveries furthered approaches to these other brain diseases as well.
“Before this, our theories about what causes schizophrenia were primitive and blaming,” said Paul Garfinkel, staff psychiatrist with the Centre for Addiction and Mental Health (CAMH). “They blamed the mother or the family dynamic. His studies showed there’s a biology to this brain illness that’s nobody’s fault.”
Dr. Seeman helped further the dopamine hypothesis of schizophrenia, which is still the prevailing theory. (At one point, scientists debated whether serotonin could be more important.)
As a professor in the Department of Pharmacology and Department of Psychiatry at the University of Toronto, Dr. Seeman also discovered that anti-psychotics that did not linger for long on the D2 dopamine receptor caused fewer side effects. He cloned four of the five known dopamine receptors, including the D2. His later research revealed that smaller doses of anti-psychotics could effectively treat schizophrenia.
The company he founded, Clera Inc., developed small-molecule therapies for schizophrenia and other dopamine-related brain diseases.
In 2000, three of his international colleagues studying dopamine won the Nobel Prize in physiology or medicine, but Dr. Seeman was left out. “He introduced hard data, hard evidence, not just theories and speculation,” said former colleague Bertha Madras, professor in the Department of Psychiatry at Harvard Medical School, suggesting that he should have received the Nobel, too.
Dr. Seeman published more than 800 articles and mentored more than 100 graduate and postdoctoral students. His research has been cited more than 55,000 times. His published papers were meticulously put together. In a tribute after his death, Dr. Madras and Susan George, professor of medicine and pharmacology and toxicology at the University of Toronto, noted that he had 1,278 references in one of his studies, all of which he acquired in hard copy and notated himself.
Dr. Madras recalled collaborating with Dr. Seeman on dopamine receptor research while she was at the University of Toronto. She was stuck on an aspect of the work, and he handed her a paper on insulin receptors that offered clues as to how to solve the problem.
“I realized he was looking at all this scientific literature that has nothing to do with the brain, to see if there were other advances that would give him insights,” Dr. Madras said. “Most scientists don’t do that. They stick to what they know.”
Dr. Seeman was half of a Canadian brain-research power couple: Mary Seeman did pioneering work on mental health and gender as a clinical researcher. “They were a real team,” his son Neil Seeman said. “They are titans in the world of brain research internationally.”
It was Mary who encouraged her husband to focus on schizophrenia early in his career, urging him to make sure his research would have an impact on patients’ lives.
He studied dopamine receptors and brain-related conditions for more than 50 years, working long after his official retirement. Dr. Philip Seeman died on Jan. 9, a month before his 87th birthday, and worked until close to his death, which was caused by the worsening of a muscular-degeneration condition he’d had for many years. In fact, the day he died, a paper he had co-authored was accepted for publication.
Philip Seeman was born on Feb. 8, 1934, in Winnipeg to father Jacob – an entrepreneur who was a tailor and owned rental properties – and mother Feige, who had both immigrated from Poland. The family, which included siblings Sandra and Stan, moved to Montreal when Philip was about 4.
He attended Baron Byng High School, and then studied physics and physiology at McGill University, graduating in 1955. He followed that up with a MSc in physiology and then started medical school at McGill.
On the first day, he sat beside Mary Szwarc, one of the eight women in the class of 100. He asked her to be in his group studying the anatomy of cadavers, but she was not interested, plus she had promised another female student they’d work together. On the sly, Philip persuaded that woman to join his group, thereby ensuring Mary would work with him.
The two also sat beside each other in histology, thanks to their surnames beginning with the same letter. “We got used to each other,” Mary recalled. While Philip was a strong student (although she got higher marks, she claims, because she studied more), he struggled with the sight of blood: He once fainted in class during a movie about childbirth and later had to leave the room while observing an operation.
The couple married in 1959, finished their MDs in 1960 and headed to Detroit for a hospital internship. Philip increasingly seemed a better fit for pure science rather than medicine. He suggested the hospital consider a new approach to assessing the acidity of blood and it adopted his idea. He could conceptualize things in three dimensions, a talent his wife recalled that she lacked. “When I looked down a microscope, I could not see anything. For him, it was all very clear,” she said.
He was accepted to the PhD program in life sciences at New York’s Rockefeller University, working under cell biologist George Emil Palade, who later shared the 1974 Nobel Prize in physiology or medicine for his discovery of ribosomes. Mary secured a residency in psychiatry at Manhattan State Hospital.
Philip’s research on electron microscopy didn’t work out, so he soon needed a new focus. “I would talk about my patients,” recalled Mary, who urged him to do work that would affect real-world patients. He became curious about schizophrenia and the new anti-psychotics used to treat the disease, so he set out to understand how they changed cells.
“We had this routine. In the morning I’d take his blood and then he’d take it down to the lab, and I’d go off to work,” she said. Philip would then isolate the red blood cells in his blood and inject them with the various anti-psychotic drugs on the market to see how they affected cell membranes.
“He discovered that the membrane expanded when these meds were given,” Mary said. Membrane expansion theory formed the basis of his PhD thesis. This concept proved important for understanding anesthesia’s impact on cells – he published a few studies on this topic – as well serving as the starting point for his work on dopamine receptors.
The family, which by then included two young sons, moved to Britain, where Philip did a year-long fellowship at the University of Cambridge. While there were other opportunities, returning to Canada became a priority for the family and he took a job at the University of Toronto in 1967.
He became a full professor there in just three years and was named chair of the Department of Pharmacology in 1977, serving in that job for a decade, and was also the head of the psychopharmacology section of the Clarke Institute of Psychiatry (now called CAMH) and held the Anne and Max Tanenbaum Chair in Neuroscience.
During these years, the Seeman family grew to include a third son, and Mary joined the staff of CAMH, became a professor at the University of Toronto and did clinical research that focused on gender differences in mental-health conditions.
It took Philip nearly a decade to isolate what would be called the dopamine D2 receptor and show how it responded to the anti-psychotic haloperidol. “At the time, it was pretty darn hard to find receptors. They exist in the brain at a very tiny level,” Dr. Madras said.
Philip remained driven to explore the dopamine D2 receptor and schizophrenia pharmacology for most of his career. “He was a compulsive person, but also a pragmatic person. He really wanted to understand and figure out how to treat this disease,” Dr. Madras said.
He received many accolades for his research, including being named a fellow of the Royal Society of Canada in 1985 and winning the Killam Prize in health sciences in 1996. He was named an officer of the Order of Canada in 2001.
Neil recalls his father getting a phone call in 2000 about the Nobel prize. “Neil, I didn’t get it,” Philip told his son, laughing, and then the two went outside to play catch.
While he was a devoted parent to his three boys – and later, his many grandchildren – he also worked long hours. “He went to the lab seven days a week. I don’t think there was a day that he didn’t go in to at least have a look to see if everything was okay,” Mary said. (Neil recalls visiting the lab often, and seeing brains preserved in freezers.)
“He was definitely a workaholic. He never would have said that. He would have just said he was enjoying himself,” she said. While he was devoted to his work, if she ever called him needing something for herself or the boys, he would drop everything.
Philip had a reputation for being a compassionate mentor to young scientists. “If you asked him anything, he had a huge amount of patience to sit down and explain it all in an easy-to-understand fashion,” Dr. Garfinkel said.
He was not concerned with the grades or reputation of his prospective lab team, Dr. Madras recalled. “He took all comers. He took people who were enthusiastic. He gave them free rein and the opportunity to prove themselves.”
Dr. Philip Seeman leaves his wife; sons, Marc, Bob and Neil; their spouses; and six grandchildren.